The present invention relates to a two-stage medicine delivery system and method for making the two-stage medicine delivery system, wherein an initial dose of medicine is capable of achieving a rapid pharmacological effect, whereas a second dose achieves a prolonged pharmacological effect. The invention also is directed to an improved methodology for symptom relief, such as relief from cravings attributable to withdrawal (e.g., nicotine withdrawal).
The term “medicine”, as used herein, is not limited to substances which relieve pain, disease and/or infection. To the contrary, the term “medicine” encompasses virtually any therapeutic substance which can be effectively applied using the system of the present invention to achieve some desired result. Similarly, the term “lozenge” as used herein is not limited to products that are hard and have a flat, diamond-like shape, but rather encompasses any candy-like source of a therapeutic substance irrespective of its shape, such as gum. The term “lozenge” includes those substitutes by which medicine may be transmucosally delivered to the user.
Most conventional medicine delivery systems have limitations which make them less than ideal. One limitation relates to the speed of delivery. Few medicine delivery systems can provide a pharmacological effect within five minutes of use, much less within one to three minutes of use, and then provide sustainable (or on-demand) delivery for over 30 minutes. The delay in pharmacological effect is especially problematic in situations where the patient takes the medication in response to a stimulus. Examples of such situations include patients who take the medication in response to heart palpitations, diabetics who take the medication in response to noticeable glucose variations, addicts who take craving-reduction medicine in response to cravings, patients who take medication in response to panic attacks, and those seeking to stop smoking and experiencing a craving for a cigarette. In those patients, dangerous complications could arise if the medication is delivered ineffectually or at too fast of a rate.
Another limitation relates to variations in concentration of medicine achieved in the user's bloodstream. Few, if any, medicine delivery systems can provide substantially constant concentrations of medicine in the bloodstream. It is desirable, however, to provide a substantially constant concentration which remains at or near the level of pharmacological effect (LPE). Concentrations below the LPE may have little, if any, effect on the symptoms which the patient wishes to alleviate. Thus, when a medicine delivery system provides such low concentration, it is doing little, if anything, to alleviate the patient. Similarly, concentrations of medicine above the LPE typically are unnecessary, and can produce side-effects or reactions to the medication. There is consequently a need for a medicine delivery system which provides an initial dose of medicine sufficient to rapidly achieve a medicine concentration in the user's bloodstream at or near the LPE and which thereafter provides another more prolonged dose capable of maintaining the concentration of medicine in the user's bloodstream substantially constant at or near the LPE.
Conventional oral delivery systems fail to provide the foregoing combination of doses and the desirable results associated therewith. Typically, the conventional oral delivery system has a delay of 1-3 hours before reaching the LPE. Thereafter, it is unable to maintain a substantially constant concentration at or near the LPE. Instead, the desired pharmacological effect is achieved over a period of time by exceeding the concentration associated with the LPE, followed by a rapid decline in concentration below the LPE.
A typical curve CC representing the concentrations achieved by such an oral delivery system is illustrated in FIG. 1. The illustrated strategy disadvantageously exposes the patient to an over-dosage, as indicated by the portion of the concentration curve CC which appears far above the LPE line. The resulting overdosage tends to produce toxic side-effects or reactions to the medication.
In addition, the concentration curve CC remains below the LPE line for a significant period of time after the medication is taken. The length of this delay may vary and is affected by the speed of ingestion. This represents a potentially unacceptable delay in the desired pharmacological effect. This delay is particularly unacceptable where the medicine is used to reduce cravings. In those situations, the delay may be long enough that the patient succumbs to the craving. Smokers, for example, might smoke before the orally taken medicine can produce a reduction in the nicotine craving.
The concentration curve CC also drops below the LPE line after the over-dosage. This likewise represents a period of time between dosages where the patient is not receiving the benefit of the desired pharmacological effect.
Although the period of time between pills can be decreased in an attempt to reduce the magnitude of the overdosages, this becomes inconvenient to the patient and greatly increases the likelihood that the patient will not comply with the dosage requirements and therefore will not receive the full benefit of the desired pharmacological effect. In order to avoid non-compliance, the medicine delivery system should minimize the amount of activity required of the patient.
An additional problem with conventional oral medicine delivery systems which require stomach absorption of the medicine is the highly volatile enzymatic environment of the gastro-intestinal system. This environment can alter the medicine and reduce or eliminate its effectiveness.
In order to provide more immediate pharmacological effects, hypodermic injection has been used as a medicine delivery system. Such injection techniques, however, fail to provide constant concentrations of the medicine in the blood over prolonged periods of time.
FIG. 2 illustrates a typical concentration curve CC′ which represents the concentration of medicine in the blood over time when a conventional hypodermic injection technique is used. The concentration curve CC′ demonstrates how the initial dosage actually exceeds the LPE necessary to achieve the desired pharmacological effect. The hypodermic injection technique therefore exposes the patient to an over-dosage. This over-dosage, in turn, increases the likelihood of side-effects and adverse reactions. Another disadvantage associated with the conventional hypodermic injection technique is that it fails to provide a prolonged period of time during which the concentration remains at or near the LPE. Instead, the concentration curve CC′ reaches a peak soon after injection and progressively diminishes over time.
Yet another disadvantage associated with conventional hypodermic injection techniques is the pain associated with such injection techniques. Some patients are extremely disturbed by the notion of hypodermic injection. This limits the number of patients which will use the injection technique. Even the patients which do elect to use the hypodermic injection technique may be less likely to comply on a regular basis with dosage requirements when faced with the unpleasantness of frequent injections. In many cases, the injection technique requires medical personnel, privacy, and/or a stationary place to perform the injection. When all three requirements are present, the injection technique is extremely inconvenient to the patient.
Another conventional technique for delivering medicine involves an intravenous drip. The intravenous drip is capable of providing a rapid pharmacological effect and can be programmed to dispense medicine at a rate which achieves a substantially constant concentration of medicine in the blood, at or near the LPE. A typical curve CC″ representing the concentrations achieved by the intravenous drip technique is illustrated in FIG. 3.
The intravenous drip, however, requires trained medical personnel to supervise the delivery of medicine. This can result in delay because medical personal usually cannot respond immediately. The requirement of medical personnel also makes the intravenous drip technique very inconvenient for the patient. Another disadvantage associated with the intravenous drip technique is the need to insert a catheter subcutaneously. The initial insertion may be painful and uncomfortable, making this technique difficult on patients. In addition, the patient's mobility may be significantly hampered during the intravenous delivery of the medicine.
The intravenous drip technique is especially difficult to implement on an effective basis when the medicine is a craving reduction medicine. In those situations, it is impractical to have the patient meet with medical personnel to have a catheter inserted every time the patient experiences a craving.
Inhalation techniques also have been used to deliver medicine. Although such techniques may provide rapid and effective pharmacological effects, it is difficult to regulate the concentration of medicine in the blood over a prolonged period of time when such techniques are used.
Another conventional technique for delivering medicine involves the use of chewing gum. The chewing gum includes a medicine which is released into the mouth when the gum is chewed. Such gums can provide a relatively constant concentration of medicine, with slight variations from that consentration, in the chewer's blood. Accordingly, the LPE can be achieved using concentrations which do not deviate much higher than the LPE and do not vary significantly from the LPE. The chewing gum-based technique therefore advantageously avoids the over-dosage problems associated with conventional, orally administered medications which are not chewed but are immediately swallowed. A typical curve CC′″ representing the concentrations achieved by the chewing gum-based delivery systems is illustrated in FIG. 4.
A disadvantage associated with conventional gum chewing techniques, however, is the delay between the time when chewing begins and onset of the desired pharmacological effect. The delay typically is caused by the time it takes for sufficient medicine to be released from the gum and for that medicine to be absorbed into the bloodstream.
In the case of gums which are used to counteract cravings for nicotine-containing products, a substantial portion of the nicotine from such gums may be swallowed because of poor absorption in the mouth. Since nicotine, when swallowed, can cause adverse gastrointestinal symptoms, such as hiccupping and nausea, the conventional chewing gum technique can produce undesirable side-effects.
If the gum fails to provide a desired level of craving relief, attempts to obtain additional nicotine from the gum may cause increased feelings of nausea because of the frequent failure of users to absorb (rather than swallow) the nicotine. Thus, the effectiveness of conventional nicotine delivery gums may be difficult to adjust upwardly without experiencing an increased potential for nausea.
Despite the disadvantages associated with conventional nicotine delivering gum, there are commercially available versions of the gum, one of which is marketed using the trademark Nicorette™. Although the sensory effects of Nicorette™ provide an initial level of craving relief which is comparable to that which is produced by confectionery chewing gum, it is the delivery of nicotine to the bloodstream which produces objectively documented effects of craving relief. The delivery of nicotine to the bloodstream generally provides discriminable effects to the user (e.g., “feel the drug”), reduced desire for smoking, restoration of cognitive performance, and reversal of withdrawal-associated EEG disruption. See e.g., Henningfield et al., Pathophysiology of Tobacco Dependence, (1995), which appears in Bloom & Kupfer, Psychopharmacology: The Fourth Generation of Progress, Raven Press, pp. 1715-1729; Benowitz, Pharmacology of Nicotine: Addition and Therapeutics, Annual Review of Pharmacology and Toxicology, 36: 597-613.
Studies on the effects of Nicorette™ provide a basis for determining the doses at which various effects occur. For example, the approximately one milligram of nicotine delivered over 15-30 minutes by the 2 milligram version of Nicorette™ provides detectable effects, with minimal risk of nausea and undesirable pharmacologic consequences for most users. When the dose is increased, for example by using the 4 milligram version of Nicorette™ (which delivers about 2 milligrams of nicotine) or by administering multiple units of Nicorette™ (up to 4 units of the 4 milligram version of Nicorette™), the reliability of the craving reduction increases, but the probability of undesirable consequences, such as dizziness and nausea, also increases.
An important finding from the foregoing studies is that the craving-reducing effects of nicotine on the body are almost exclusively due to the nicotine which is absorbed into the bloodstream. Nicotine which remains in the saliva and/or is swallowed has very little effect beyond its flavor-induced sensory effects and stomach upset produced by excessive amounts of swallowed nicotine.
Nicotine from Nicorette™ reaches the bloodstream in several different ways. See e.g., Benowitz & Savanapridi, Determinants of Nicotine Intake While Chewing Nicotine Polacrilex Gum, Clinical Pharmacology and Therapeutics, 41(4), pp. 467-473. About 50% of the nicotine from the 2 and 4 milligram versions of the Nicorette™ is released from the gum during chewing. The rest of the nicotine typically remains in the gum and is discarded by the user.
Of the nicotine delivered by the 2 milligram version of the Nicorette™ gum to the saliva, about 0.8 milligram is absorbed through the membranes of the mouth (the buccal mucosa) and appears in the bloodstream. The remaining approximately 0.2 milligram is swallowed, of which 0.06 milligram survives first pass hepatic metabolism and appears in the bloodstream. The 4 milligram version of Nicorette™ gum achieves nicotine absorption values which are approximately twice those of the 2 milligram version.
Although the amount of nicotine absorption from Nicorette™ is related to the chewing rate and the time the saliva is held in the mouth, these variables are significant only at the extremes of rapid chewing versus little oral action, and frequent swallowing versus infrequent swallowing. Outside of such extremes, these variables have very little impact on nicotine absorption. Thus, it takes approximately 10 to 30 minutes to achieve absorption of the nicotine from Nicorette™ into the bloodstream, regardless of whether the “park and chew” (or “chew and park”) method is used or chewing at regular intervals (e.g., one chew per 4 seconds).
This initial delay, however, may be excessively long for someone who is trying to quit smoking. It is not unusual for a cigarette smoker to succumb to a nicotine craving within ten minutes of onset, especially if work or a stressful situation delays the use of the Nicorette™ beyond initial onset of the craving.
There is consequently a need for a nicotine delivery system which avoids the disadvantages associated with Nicorette™ gum (e.g., the initial delay in nicotine delivery) by providing rapid craving relief and which therefore minimizes the likelihood that a former smoker will succumb to his craving.
In providing such a nicotine delivery system, the documented effects of conventional nicotine sources, such as Nicorette™ gum, cigarettes, cigars, transdermal patches, and snuff have been considered to arrive at a delivery system which provides beneficial absorption characteristics.
Scientific data on the determinants of nicotine absorption through the membranes of the mouth, nose and epidermis, has been studied in detail since at least the 1940s. Much of this work has been reviewed in detail by the U.S. Food and Drug Administration (FDA). S. L. Tomar & J. E. Henningfield, for example, prepared a report entitled Review of the Evidence that pH is a Determinant of Nicotine Dosage from Oral use of smokeless Tobacco, Tobacco Control, 6:219-225 (1997).
Based on the various studies, including studies of the epidermis and the buccal mucosa, the two major determinants of nicotine absorption are (1) the concentration of nicotine solution on the membrane and (2) the pH of the nicotine solution. The importance of these two determinants transcends a broad range of nicotine-containing applications, including transdermal patches, the nicotine-containing aerosol from tobacco smoke or the vapor inhaler marketed by Pharmacia, the micro environment of nicotine and moisture between the user's gum and cheek when moist snuff products are used, as well as the saliva-nicotine solution produced when Nicorette™ gum is chewed.
In the case of transdermal patches, for example, the initial form of dose control is provided by regulating the amount of nicotine which is applied against the epidermis. Once a predetermined amount of nicotine reaches the dermal membrane, the pH of the nicotine-containing solution determines the speed of absorption.
The Nicoderm™ patch, for example, carries 1-4 milligrams of nicotine in its surface layer to provide an initial burst of nicotine. The initial burst of nicotine is then followed by a controlled release from the patch reservoir. While the initial burst of nicotine is relatively rapid when compared to that provided by most other commercially available transdermal nicotine patches, it is still slow (about 30 minutes to achieve a significant increase in nicotine blood level) when compared to what can be achieved by delivery through the mouth. Dose-ranging studies were performed to determine the optimal amount of nicotine and amount and type of buffer to maximize absorption and to minimize skin irritation.
The relationship of the pH to the absorption rate of nicotine also was documented by O. Femo in 1977, who concluded that unbuffered formulations were ineffective at nicotine delivery or relieving withdrawal symptoms. See Femo, Development of a Chewing Gum Containing Nicotine and Some Comments on the Role Played by Nicotine in the Smoking Habit, in Steinfeld et al., Smoking& Health, Proceeding of the 3rd World Conference on Smoking and Health, Washington, D.C. (1977).
This led to the addition of 30 milligrams of sodium-based buffers to the gum formulations. The 2 milligram version of Nicorette™, for example, contains 10 milligrams of sodium bicarbonate and 20 milligrams of sodium carbonate. The 4 milligram version of Nicorette™ contains 30 milligrams of sodium carbonate.
The combination of buffers in Nicorette™ raises oral salivary pH from its typical value of about 6.9-7.3 to about 8.0 in 5-10 minutes. The act of chewing itself contributes to the rise in pH because chewing-stimulated saliva from the parotid gland contains some bicarbonate. By comparison, chewing an anti-acid tablet marketed under the trademark Tums™ (which contains calcium carbonate), produces an almost immediate increase in oral salivary pH to about 8.1.
Since Nicorette™ is physio-chemically structured so that its nicotine is evenly distributed throughout the gum, the release of nicotine depends on exposing fresh surface areas of the gum to the salivary substrate so that nicotine and buffer can be released into the saliva. The portion of nicotine which is unionized is free to be immediately absorbed through the buccal mucosa. Because the dissociation constant (pKa) of nicotine is 8.0, fifty percent of the nicotine is unionized and immediately free to be absorbed when the solution is at a pH of 8.0. At this pH, residual nicotine becomes unionized as the free nicotine is absorbed. There is consequently a steady but very rapid infusion of nicotine across the membrane after the appropriate pH is reached.
There have been several practical applications of the foregoing principles which provide guidance regarding the dosing range and speed for nicotine delivery systems. At least one of the “active” Nicorette™ placebo formulations used in the 1980s and early 1990s, for example, contained 0.5 milligram of nicotine without any buffer and was a useful placebo because it produced the oral sensory effects of nicotine with minimal absorption. Unlike chewing tobacco, which is actively chewed, moist snuff is used according to instructions from the major marketers of these products in a manner that is functionally similar to the chew and park method for Nicorette™. The physical effort required to manipulate the moist snuff, however, is less than that required by Nicorette™. The instructions direct the user to place the dose between the gum and cheek, and occasionally move or otherwise orally manipulate it. When such products are used, large differences in nicotine absorption have been observed as a function of two variables, namely, nicotine concentration and pH.
The relationship between pH and absorption rate is further illustrated by the differences between cigar smoke and cigarette smoke. Cigar smoke can provide rapid delivery of nicotine when held in the mouth because cigar smoke typically has a pH in the range of 7.5 to 8.0. Cigarette smoke, by contrast, typically has a pH between 5.5 and 6.0 and therefore must be inhaled to produce effective absorption. It is believed that effective nicotine absorption does not require pH levels greater than approximately 8.5 to 9.5. Further increases above 9.5 would be expected to produce a soapy and/or burning sensation in the mouth.
A need therefore exists for a nicotine delivery system which rapidly elevates a pH level in the user's mouth so that rapid absorption of nicotine into the bloodstream can be achieved, and which also delivers nicotine over a prolonged period of time to maintain a pharmacologically appropriate concentration of nicotine in the bloodstream.